Although several laboratories have identified cardiac progenitor cells (CPCs), the controversy concerning myocyte regeneration in the adult heart has not been resolved. Similarly, the plasticity of bone marrow derived progenitor cells (BMPCs) and their ability to acquire the myocyte lineage and regenerate dead myocardium has been challenged. Therefore, one of the major objectives of this application is to determine by a novel approach that involves genetic tagging and clonal marking, whether c-kit-positive BMPCs and CPCs acquire a cardiac phenotype and give rise to a large number of myocyte-committed progeny. The therapeutic efficacy of these two classes of progenitor cells for acute and chronic ischemic heart failure depends on their ability (a) to survive in the hostile milieu of the damaged heart, (b) to engraft within the myocardium, and (c) to grow and differentiate. BMPCs may have a growth potential, which is superior to CPCs but transdifferentiation could affect this characteristic and CPCs may constitute a more powerful form of therapy for cardiac repair. The process of transdifferentiation may alter the growth behavior of BMPCs, which may lose in part their capability of dividing through alterations of the telomere-telomerase system, premature cellular senescence, and apoptosis. Similarly, myocytes derived from BMPCs may possess inherent limitations in the acquisition of the adult phenotype. The opposite may also be true and BMPCs may retain even after transdifferentiation a stronger regenerative capacity than CPCs representing the most appropriate cells for the damaged heart. With BMPCs, the newly formed myocytes appear to have fetal- neonatal properties and may not reach the adult phenotype, a problem that may not affect the commitment of CPCs. Relative hypoxia at the1 border and infarct may modulate the Notch pathway, and prolonged Notch activation may inhibit downregulation of Nkx2.5 and, thereby, the transition from early to late myocyte differentiation. Notch may repress transcription of GATA4, which could be critical for irreversible myocyte commitment. This behavior conforms to a model of differentiation delay in which the persistence of Notch opposes the progression of maturation. Ultimately, the proposed work addresses the question whether BMPCs are superior, equal, or inferior to CPCs for the regeneration of cardiomyocytes and coronary vessels in ischemic heart failure. ? ? ?
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